JPH0115492B2 - - Google Patents
Info
- Publication number
- JPH0115492B2 JPH0115492B2 JP55049956A JP4995680A JPH0115492B2 JP H0115492 B2 JPH0115492 B2 JP H0115492B2 JP 55049956 A JP55049956 A JP 55049956A JP 4995680 A JP4995680 A JP 4995680A JP H0115492 B2 JPH0115492 B2 JP H0115492B2
- Authority
- JP
- Japan
- Prior art keywords
- dimethoxy
- acid
- reaction
- solvent
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000004053 quinones Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 150000001875 compounds Chemical class 0.000 description 37
- 239000002904 solvent Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 239000013078 crystal Substances 0.000 description 18
- -1 alkyl radicals Chemical class 0.000 description 16
- 238000000921 elemental analysis Methods 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 238000010531 catalytic reduction reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 150000002978 peroxides Chemical class 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KCIZTNZGSBSSRM-UHFFFAOYSA-N 3,4,5-Trimethoxytoluene Chemical compound COC1=CC(C)=CC(OC)=C1OC KCIZTNZGSBSSRM-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 235000017471 coenzyme Q10 Nutrition 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- UIXPTCZPFCVOQF-UHFFFAOYSA-N ubiquinone-0 Chemical compound COC1=C(OC)C(=O)C(C)=CC1=O UIXPTCZPFCVOQF-UHFFFAOYSA-N 0.000 description 3
- 150000003669 ubiquinones Chemical class 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 229940005561 1,4-benzoquinone Drugs 0.000 description 2
- VTVIVMHHJLFDGV-UHFFFAOYSA-N 11-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)undecyl acetate Chemical compound COC1=CC(C)=C(CCCCCCCCCCCOC(C)=O)C(O)=C1OC VTVIVMHHJLFDGV-UHFFFAOYSA-N 0.000 description 2
- QXZWZZBHXKZRMK-UHFFFAOYSA-N 2-(11-hydroxyundecyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCCO)=C(C)C1=O QXZWZZBHXKZRMK-UHFFFAOYSA-N 0.000 description 2
- OQZGYMRYZAKXAF-UHFFFAOYSA-N 2-(4-methylcyclohexyl)acetic acid Chemical compound CC1CCC(CC(O)=O)CC1 OQZGYMRYZAKXAF-UHFFFAOYSA-N 0.000 description 2
- ZLJMXIBJTRTNGX-UHFFFAOYSA-N 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid Chemical compound COC1=CC(C)=C(CCCCCCCCCCCCCCCCCCCCCC(O)=O)C(O)=C1OC ZLJMXIBJTRTNGX-UHFFFAOYSA-N 0.000 description 2
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 2
- 235000021357 Behenic acid Nutrition 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- JTXBOVQAJSCRCN-UHFFFAOYSA-N [2-(10-chloro-10-oxodecyl)-5,6-dimethoxy-3-methylphenyl] acetate Chemical compound COC1=CC(C)=C(CCCCCCCCCC(Cl)=O)C(OC(C)=O)=C1OC JTXBOVQAJSCRCN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 229940116226 behenic acid Drugs 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- KFEVDPWXEVUUMW-UHFFFAOYSA-N docosanoic acid Natural products CCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 KFEVDPWXEVUUMW-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- YXARHTVZLYLEBO-UHFFFAOYSA-N methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)-22-oxodocosanoate Chemical compound COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)C1=C(C)C=C(OC)C(OC)=C1O YXARHTVZLYLEBO-UHFFFAOYSA-N 0.000 description 2
- KCYLBACXGRWNLZ-UHFFFAOYSA-N methyl 22-chloro-22-oxodocosanoate Chemical compound COC(=O)CCCCCCCCCCCCCCCCCCCCC(Cl)=O KCYLBACXGRWNLZ-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- KGIZSOWPDDQVIC-UHFFFAOYSA-N (18-chloro-18-oxooctadecyl) acetate Chemical compound CC(=O)OCCCCCCCCCCCCCCCCCC(Cl)=O KGIZSOWPDDQVIC-UHFFFAOYSA-N 0.000 description 1
- JMSUNAQVHOHLMX-UHFFFAOYSA-N 1-cyclohexylethanol Chemical compound CC(O)C1CCCCC1 JMSUNAQVHOHLMX-UHFFFAOYSA-N 0.000 description 1
- XWNQGUZMGHYHDY-UHFFFAOYSA-N 10-(2-acetyloxy-3,4-dimethoxy-6-methylphenyl)decanoic acid Chemical compound COC1=CC(C)=C(CCCCCCCCCC(O)=O)C(OC(C)=O)=C1OC XWNQGUZMGHYHDY-UHFFFAOYSA-N 0.000 description 1
- UHSRWOOHHJVERW-UHFFFAOYSA-N 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoic acid Chemical compound COC1=CC(C)=C(CCCCCCCCCC(O)=O)C(O)=C1OC UHSRWOOHHJVERW-UHFFFAOYSA-N 0.000 description 1
- XBEOUEGMKQHDGX-UHFFFAOYSA-N 11-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)undecyl acetate Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCCOC(C)=O)=C(C)C1=O XBEOUEGMKQHDGX-UHFFFAOYSA-N 0.000 description 1
- SOOWXRNIQPDZDQ-UHFFFAOYSA-N 11-hydroxy-1-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)undecan-1-one Chemical compound COC1=CC(C)=C(C(=O)CCCCCCCCCCO)C(O)=C1OC SOOWXRNIQPDZDQ-UHFFFAOYSA-N 0.000 description 1
- ROKZGSPQZDGVDC-UHFFFAOYSA-N 13-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)tridecanoic acid Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCCCC(O)=O)=C(C)C1=O ROKZGSPQZDGVDC-UHFFFAOYSA-N 0.000 description 1
- HTRUXKYPNFNXQZ-UHFFFAOYSA-N 16-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)hexadecanoic acid Chemical compound COC1=CC(C)=C(CCCCCCCCCCCCCCCC(O)=O)C(O)=C1OC HTRUXKYPNFNXQZ-UHFFFAOYSA-N 0.000 description 1
- QZNGLABJHJNKBX-UHFFFAOYSA-N 18-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)octadecyl acetate Chemical compound COC1=CC(C)=C(CCCCCCCCCCCCCCCCCCOC(C)=O)C(O)=C1OC QZNGLABJHJNKBX-UHFFFAOYSA-N 0.000 description 1
- GIMHNWHJOOSZRN-UHFFFAOYSA-N 18-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)octadecanoic acid Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCC(O)=O)=C(C)C1=O GIMHNWHJOOSZRN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C66/00—Quinone carboxylic acids
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
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-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
- C07C46/08—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring with molecular oxygen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C50/28—Quinones containing groups having oxygen atoms singly bound to carbon atoms with monocyclic quinoid structure
-
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
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Description
本発明は医薬として有用な新規キノン類に関す
る。
ユビキノン類は心不全、歯周症、糖尿病、筋ジ
ストロフイー、喘息などに有効であるが、一般に
水溶性が低いため投与法が限定され、薬効発現の
上でも問題がある。本発明者らはキノン誘導体に
ついて種々検討した結果、優れた薬効を奏する新
規キノン類を見いだした。
すなわち、本発明は、一般式
〔式中、ｎは10〜21の整数、Ｒは水素または低級
アルキル基を示す〕で表わされるキノン類に関す
る。
前記一般式（）中Ｒで示される低級アルキル
基としては、たとえばメチル、エチル、ｎ−プロ
ピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチル、
ｔ−ブチルなど炭素数１〜４のものがあげられ
る。
本発明の化合物（）は、(1)式
で表わされる化合物と一般式
ROCO（CH2）nCOOH （）
〔式中、Ｒおよびｎは前記と同意義〕で表わされ
るカルボン酸もしくはその無水物の過酸化物とを
反応させる〔以下製造方法(1)という〕か、(2)一般
式
〔式中、Ｒおよびｎは前記と同意義〕で表わされ
る化合物を酸化する〔以下製造方法(2)という〕
か、または(3)一般式
〔式中、ｎは前記と同意義〕で表わされる化合物
を酸化し、所望によりエステル化する〔以下製造
方法(3)という〕ことにより製造することができ
る。
上記製造方法(1)は化合物（）と化合物（）
もしくはその無水物の過酸化物〔以下化合物
（′）の過酸化物ということもある〕を反応させ
ることによつて行なわれる。化合物（′）の過
酸化物としては、加熱することによつて炭酸ガス
を発生してアルキルラジカルを生じるようなもの
ならばどのようなものでもよく、たとえばカルボ
ン酸、そのハロゲン化物または酸無水物にたとえ
ば過酸化水素、その金属塩、四酢酸鉛などの過酸
化物を作用させることにより得ることができる。
製造方法(1)の反応は適宜の不活性溶媒、たとえ
ばｎ−ヘキサン、リグロイン、トルエン、キシレ
ン、酢酸、プロピオン酸中で行うのが好ましい。
反応温度は約80゜〜100℃が好ましく、反応時間は
約0.5〜３時間が好ましい。本反応は炭酸ガスの
発生とともに、きわめて緩和な条件下に進行し、
副反応が少なく、目的物が好収率で得られ、ま
た、反応後未反応の原料は損失することなく回収
される。
また該反応は反応系中に過酸化物が生成するよ
うな条件下で行つてもよく、たとえば、四価鉛化
合物（たとえば四酢酸鉛）などの存在下に化合物
（）と化合物（）もしくはその無水物とを反
応させることによつて行われる。該反応は適宜の
不活性溶媒（たとえばｎ−ヘキサン、リグロイ
ン、トルエン、キシレン、酢酸、プロピオン酸な
ど）中で行うのが好ましく、また反応温度は50゜
〜150℃が好ましい。
上記製造方法(2)の反応は化合物（）を酸化す
ることによつて行われる。酸化反応における酸化
手段としては一般にフエノール類をキノン類に導
くことができるものがいずれも便宜に使用でき
る。酸化剤としては具体的には、たとえば塩化第
二鉄、酸化銀、二酸化マンガン、過酸化水素、過
酢酸、過ギ酸、過安息香酸、過マンガン酸カリウ
ム、重クロム酸カリウム、無水クロム酸、ニトロ
ソジスルホン酸カリウム、コバルト錯体／酸素な
どが挙げられる。当該反応は通常適宜の溶媒の存
在下に行なわれる。そのような溶媒としては反応
を妨げないものならどのようなものでもよいが、
具体的にはたとえば水、希酸あるいは希アルカリ
水溶液、アセトン、エタノール、ジオキサン、エ
ーテル、酢酸、ハロゲン化炭化水素、Ｎ，Ｎ−ジ
メチルホルムアミド、ヘキサメチルホスホトリア
ミドなどが挙げられる。反応の進行状態は薄層ク
ロマトグラフイーにより、知ることができる。こ
の場合、黄色の呈色像、ロイコメチレンブルー試
薬による呈色反応、あるいは紫外部吸収スペクト
ルが確認手段として採用されうる。反応温度、反
応時間は用いる酸化剤の種類などによつて多少異
なるが、通常反応温度は約０〜50℃が、反応時間
は約0.5時間〜10日間程度が好ましい。また適当
な緩衝液（たとえばリン酸緩衝液など）の存在の
もとに反応を行なうことによつても好結果が得ら
れる。
上記製造方法(3)の反応は化合物（）を酸化
し、必要によりこれをエステル化することにより
行われる。酸化は自体公知の手段により行われ、
側鎖の水酸基を酸化してカルボキシル基に変換し
うるものがいずれも採用される。酸化剤として
は、たとえば二酸化マンガン、クロム酸などが好
ましく用いられる。反応は、たとえば硫酸、塩酸
などの鉱酸、たとえばピリジンなどの塩基の存在
下に行つてもよい。この酸化反応により一般式
（）中Ｒが水素である化合物が得られる。した
がつて、一般式（）中Ｒが低級アルキル基であ
る化合物を得たい場合は、酸化反応によつて得ら
れる化合物をエステル化すればよい。かかるエス
テル化反応としてはカルボン酸類またはそのカル
ボキシル基における反応性誘導体とアルコール
類、フエノール類、ハロゲン化アルキル類、ハロ
ゲン化アラルキル類、ジアルキル硫酸あるいはジ
メゾメタンとを反応させる方法などがあげられ
る。カルボン酸類の反応性誘導体としてはカルボ
ン酸無水物、カルボン酸ハライド、カルボン酸低
級アルコールエステル、カルボン酸のナトリウ
ム、カリウム、銀などの金属塩などがあげられ、
アルコール類としてはたとえば、メタノール、エ
タノール、プロパノール、イソプロパノール、ブ
タノール、イソブタノール、シクロヘキシルメチ
ルカルビノールなど、ハロゲン化アルキルとして
はたとえばヨー化メチル、ヨー化エチルなどがあ
げられる。
このように上記製造方法(1)、(2)または(3)によつ
て化合物（）を製造することができる。製造方
法(1)または(2)によつて得た化合物（）のＲが水
素原子である場合は、必要により前記製造方法(2)
のエステル化反応と同様にしてＲが低級アルキル
である化合物（）に変換することができる。ま
たキノン類（）のＲが低級アルキル基である場
合には自体公知の手段により加水分解することに
よつて、Ｒが水素原子であるキノン類（）に導
びくことができる。かかる加水分解反応はたとえ
ば鉱酸（硫酸、塩酸など）、アルカリ性物質（水
酸化ナトリウム、水酸化カリウム、水酸化カルシ
ウムなど）などの存在下で好都合に実施される。
また、適当な抗酸化剤（ピロガロールなど）、還
元剤（ハイドロサルフアイトなど）の存在下に加
水分解を行い生成する一般式
〔式中、Ｒおよびｎは前記と同意義〕で表わされ
る化合物をたとえば塩化第二鉄、酸化銀、空気な
どで酸化することによつてもＲが水素原子である
化合物（）を得ることができる。
かくして得られたキノン類（）は自体公知の
手段、たとえば、液性変換、転溶、濃縮、減圧蒸
留、クロマトグラフイー、結晶化、再結晶など適
宜の採取手段により、容易に採取しうる。
なお、キノン類（）のＲが水素原子である場
合は、キノン類（）は遊離のカルボン酸の形態
で採取されてもよいし、薬理学的に許容される塩
の形態で採取されてもよい。遊離のカルボン酸は
採取後、塩に変換してもよい。そのような塩とし
ては具体的には金属塩、たとえばナトリウム塩、
カリウム塩等のアルカリ金属塩、たとえばマグネ
シウム塩、カルシウム塩等のアルカリ土類金属
塩、アルミニウム塩、たとえばアンモニウム塩、
トリメチルアミン塩、トリエチルアミン塩等のア
ミン塩が挙げられる。
製造方法(2)の原料化合物（）はたとえば次式
で示されるように化合物（）と化合物（）と
をフリーデルクラフト反応に付して化合物（）
を得、ついでこれを還元することによつて得るこ
とができる。
〔一般式（）、（）中、Ｒおよびｎは前記と同
意義〕
化合物（）と化合物（）との反応は適宜の
触媒の存在下に行うのが有利であり、かかる触媒
としてはフリーデルクラフト反応に用いられる触
媒ならどのようなものでもよく、たとえば硫酸、
リン酸、ポリリン酸などの鉱酸、塩化アルミニウ
ム、三フツ化ホウ素などのルイス酸などが好んで
用いられる。反応は溶媒なしでも進行するが、通
常不活性有機溶媒中行なわれ、たとえばニトロベ
ンゼン、二硫化炭素、ジクロルメタン、１，２−
ジクロルエタン、テトラクロルエタンなどが用い
られる。反応温度は約０〜150℃が好ましい。化
合物（）を還元する方法としては化合物（）
中のカルボニル基をメチレン基に導くことができ
るものがいずれも便宜に使用できる。そのうち、
好ましい例として、たとえば亜鉛アマルガムと塩
酸によるクレメンゼン還元、ケトンをヒドラゾン
となし塩基の存在下に分解するウオルフキシユナ
ー還元、ジチオアセタートとなしニツケルで脱硫
的に還元する方法、接触還元あるいは水素化ホウ
素ナトリウムでヒドロキシ基に還元したのち接触
還元に付す方法などをあげることができる。当該
反応は通常適宜の溶媒の存在下に行なうのが有利
である。そのような溶媒は反応に関係しないもの
ならどのようなものでもよいが、具体的にはたと
えばエーテル、メタノール、エタノール、ベンゼ
ン、トルエン、キシレン、エチレングリコール、
トリエチレングリコール、酢酸などが挙げられ
る。これらの還元方法は一般常法に従つて容易に
行なわれるが、たとえば還元手段として接触還元
を採用した場合についてさらに詳しく述べると、
触媒としてはパラジウム−炭素、酸化白金、ラネ
ーニツケル、ロジウム−炭素などの接触還元に使
用される触媒が用いられる。反応に用いる溶媒と
しては、たとえば酢酸エチルなどの酢酸エステル
類、メタノールなどのアルコール類あるいはギ
酸、酢酸などの有機酸が好ましい。本還元反応は
たとえば塩酸、過塩素酸、ｐ−トルエンスルホン
酸などの存在下に行うことにより反応を促進する
こともできる。反応温度は0゜〜150℃の範囲が用
いられ、通常は室温で行われる。水素の圧力は１
気圧から150気圧の範囲で、とりわけ１気圧が好
ましい。
また化合物（）は下記の方法によつても製造
することができる。
（式中、m2は３〜19の整数を示し、m1は０〜16
の整数のうちm1＋m2が８〜19となる整数を示
す）
上記製造方法(3)の原料化合物（）は、たとえ
ば次式で示される方法によつて製造することがで
きる。
一般式（）で示される本発明化合物はユビキ
ノン類の生理作用を示し、ユビキノン類の生理作
用の測定法として一般に用いられている方法でミ
トコンドリア電子伝達能を測定した結果、第一表
に示すように顕著な活性が認められた。
The present invention relates to novel quinones useful as pharmaceuticals. Ubiquinones are effective for heart failure, periodontal disease, diabetes, muscular dystrophy, asthma, etc., but their low water solubility generally limits their administration methods and poses problems in terms of their efficacy. As a result of various studies on quinone derivatives, the present inventors discovered a new quinone that exhibits excellent medicinal effects. That is, the present invention provides the general formula It relates to quinones represented by [wherein n is an integer of 10 to 21, and R represents hydrogen or a lower alkyl group]. Examples of the lower alkyl group represented by R in the general formula () include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
Examples include those having 1 to 4 carbon atoms such as t-butyl. The compound () of the present invention has the formula (1) A compound represented by the formula: ROCO(CH 2 ) nCOOH () [wherein R and n have the same meanings as above] is reacted with a peroxide of a carboxylic acid or its anhydride [hereinafter the production method ( 1) or (2) general formula Oxidize the compound represented by [wherein R and n have the same meanings as above] [hereinafter referred to as production method (2)]
or (3) general formula It can be produced by oxidizing the compound represented by [wherein n has the same meaning as above] and optionally esterifying it [hereinafter referred to as production method (3)]. The above manufacturing method (1) is a compound () and a compound ().
Alternatively, it is carried out by reacting a peroxide of the anhydride (hereinafter also referred to as a peroxide of compound (')). The peroxide of compound (') may be any substance that generates carbon dioxide gas and alkyl radicals when heated, such as carboxylic acids, their halides, or acid anhydrides. It can be obtained by reacting a peroxide such as hydrogen peroxide, a metal salt thereof, or lead tetraacetate. The reaction in production method (1) is preferably carried out in an appropriate inert solvent, such as n-hexane, ligroin, toluene, xylene, acetic acid, or propionic acid.
The reaction temperature is preferably about 80° to 100°C, and the reaction time is preferably about 0.5 to 3 hours. This reaction proceeds under extremely mild conditions with the generation of carbon dioxide gas,
There are few side reactions, the target product is obtained in good yield, and unreacted raw materials are recovered after the reaction without loss. The reaction may also be carried out under conditions where peroxide is produced in the reaction system, for example, compound () and compound () or its This is done by reacting with anhydride. The reaction is preferably carried out in a suitable inert solvent (eg, n-hexane, ligroin, toluene, xylene, acetic acid, propionic acid, etc.), and the reaction temperature is preferably 50° to 150°C. The reaction in the production method (2) above is carried out by oxidizing the compound (). As an oxidation means in the oxidation reaction, any method that can generally lead phenols to quinones can be conveniently used. Specific examples of oxidizing agents include ferric chloride, silver oxide, manganese dioxide, hydrogen peroxide, peracetic acid, performic acid, perbenzoic acid, potassium permanganate, potassium dichromate, chromic anhydride, and nitrosate. Examples include potassium disulfonate and cobalt complex/oxygen. The reaction is usually carried out in the presence of a suitable solvent. Any solvent may be used as long as it does not interfere with the reaction, but
Specific examples include water, dilute acid or dilute alkali aqueous solutions, acetone, ethanol, dioxane, ether, acetic acid, halogenated hydrocarbons, N,N-dimethylformamide, hexamethylphosphotriamide, and the like. The progress of the reaction can be determined by thin layer chromatography. In this case, a yellow color image, a color reaction using a leucomethylene blue reagent, or an ultraviolet absorption spectrum may be employed as confirmation means. Although the reaction temperature and reaction time vary somewhat depending on the type of oxidizing agent used, the reaction temperature is usually about 0 to 50°C, and the reaction time is preferably about 0.5 hours to 10 days. Good results can also be obtained by carrying out the reaction in the presence of a suitable buffer (eg, phosphate buffer). The reaction of the above production method (3) is carried out by oxidizing the compound () and, if necessary, esterifying it. Oxidation is carried out by means known per se,
Any compound whose side chain hydroxyl group can be oxidized and converted into a carboxyl group can be used. As the oxidizing agent, for example, manganese dioxide, chromic acid, etc. are preferably used. The reaction may be carried out in the presence of a mineral acid such as sulfuric acid or hydrochloric acid, or a base such as pyridine. This oxidation reaction yields a compound in which R in the general formula () is hydrogen. Therefore, when it is desired to obtain a compound in which R in the general formula () is a lower alkyl group, the compound obtained by an oxidation reaction may be esterified. Examples of such an esterification reaction include a method in which carboxylic acids or their reactive derivatives at the carboxyl group are reacted with alcohols, phenols, halogenated alkyls, halogenated aralkyls, dialkyl sulfuric acid, or dimezomethane. Examples of reactive derivatives of carboxylic acids include carboxylic acid anhydrides, carboxylic acid halides, carboxylic acid lower alcohol esters, and metal salts of carboxylic acids such as sodium, potassium, and silver.
Examples of alcohols include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and cyclohexylmethylcarbinol, and examples of alkyl halides include methyl iodide and ethyl iodide. In this way, compound () can be produced by the above production method (1), (2) or (3). When R in the compound () obtained by production method (1) or (2) is a hydrogen atom, the above production method (2) may be used as necessary.
It can be converted to a compound () in which R is lower alkyl in the same manner as the esterification reaction. Furthermore, when R in the quinones () is a lower alkyl group, the quinones () in which R is a hydrogen atom can be obtained by hydrolysis by means known per se. Such hydrolysis reactions are conveniently carried out, for example, in the presence of mineral acids (sulfuric acid, hydrochloric acid, etc.), alkaline substances (sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.).
In addition, the general formula produced by hydrolysis in the presence of an appropriate antioxidant (pyrogallol, etc.) and reducing agent (hydrosulfite, etc.) A compound () in which R is a hydrogen atom can also be obtained by oxidizing a compound represented by [wherein R and n have the same meanings as above] with, for example, ferric chloride, silver oxide, air, etc. can. The quinones () thus obtained can be easily collected by suitable collection methods known per se, such as liquid conversion, dissolution, concentration, vacuum distillation, chromatography, crystallization, and recrystallization. In addition, when R of quinones () is a hydrogen atom, quinones () may be collected in the form of a free carboxylic acid or in the form of a pharmacologically acceptable salt. good. After collection, the free carboxylic acid may be converted into a salt. Specifically, such salts include metal salts, such as sodium salts,
Alkali metal salts such as potassium salts, alkaline earth metal salts such as magnesium salts, calcium salts, aluminum salts such as ammonium salts,
Examples include amine salts such as trimethylamine salt and triethylamine salt. The raw material compound () in production method (2) is obtained by subjecting compound () and compound () to a Friedel-Crafts reaction, for example, as shown in the following formula.
can be obtained by obtaining and then reducing it. [In general formulas () and (), R and n have the same meanings as above] The reaction between compound () and compound () is advantageously carried out in the presence of an appropriate catalyst, such as Friedel et al. Any catalyst used in Kraft reactions may be used, such as sulfuric acid,
Mineral acids such as phosphoric acid and polyphosphoric acid, Lewis acids such as aluminum chloride and boron trifluoride, and the like are preferably used. Although the reaction can proceed without a solvent, it is usually carried out in an inert organic solvent, such as nitrobenzene, carbon disulfide, dichloromethane, 1,2-
Dichloroethane, tetrachloroethane, etc. are used. The reaction temperature is preferably about 0 to 150°C. Compound () is a method for reducing compound ().
Any compound whose carbonyl group therein can be converted into a methylene group can be conveniently used. One of these days,
Preferred examples include, for example, Clemensen reduction with zinc amalgam and hydrochloric acid, Wolffxyner reduction in which a ketone is decomposed into a hydrazone in the presence of a base, desulfurization reduction with dithioacetate and pure nickel, catalytic reduction or with sodium borohydride. Examples include a method of reducing to a hydroxy group and then subjecting it to catalytic reduction. It is usually advantageous to carry out the reaction in the presence of a suitable solvent. Such a solvent may be any solvent that is not involved in the reaction, but specific examples include ether, methanol, ethanol, benzene, toluene, xylene, ethylene glycol,
Examples include triethylene glycol and acetic acid. These reduction methods are easily carried out according to general methods, but for example, if catalytic reduction is used as the reduction method, we will discuss in more detail:
As the catalyst, catalysts used in catalytic reduction such as palladium-carbon, platinum oxide, Raney nickel, and rhodium-carbon are used. The solvent used in the reaction is preferably, for example, acetic acid esters such as ethyl acetate, alcohols such as methanol, or organic acids such as formic acid or acetic acid. This reduction reaction can also be promoted by performing it in the presence of, for example, hydrochloric acid, perchloric acid, p-toluenesulfonic acid, or the like. The reaction temperature used is in the range of 0° to 150°C, and is usually carried out at room temperature. The pressure of hydrogen is 1
The range is from 1 atm to 150 atm, with 1 atm being particularly preferred. Compound () can also be produced by the following method. (In the formula, m 2 represents an integer from 3 to 19, and m 1 represents an integer from 0 to 16
m 1 +m 2 represents an integer of 8 to 19) The raw material compound ( ) of the above production method (3) can be produced, for example, by the method shown by the following formula. The compound of the present invention represented by the general formula () exhibits the physiological effects of ubiquinones, and the mitochondrial electron transport ability was measured using a method generally used to measure the physiological effects of ubiquinones, as shown in Table 1. Remarkable activity was observed in
【表】
一方、本発明化合物について、喘息の主要な原
因の一つにあげられているスロー・リアクテイン
グ・サブスタンス・オブ・アナフイラキシス
〔slow reacting substance of anaphylaxis（以
下SRS−Ａと略す）〕の産生、放出に及ぼす効果
をしらべた。すなわち、オレンジ（Orange）お
よびモーレ（Moore）の方法（J.Immunol.、116
巻、392−397頁、1976年）にならい、抗原として
卵白アルブミンで感作したモルモツトの肺切片に
本発明化合物と同時に抗原を添加しその際産生、
放出されるSRS−Ａ量をブロツクレフルスト
（Brocklehurst）（J.Physiol.、151巻、416頁−
435頁、1960年）の方法で測定した。その結果、
第二表に示すように本件化合物は低濃度において
極めて強いSRS−Ａ産生抑制作用を示した。[Table] On the other hand, the compound of the present invention has been shown to be effective against slow reacting substances of anaphylaxis (hereinafter abbreviated as SRS-A), which is one of the major causes of asthma. The effects on production and release were investigated. namely, the method of Orange and Moore (J.Immunol., 116).
Vol., pp. 392-397, 1976), the antigen was added at the same time as the compound of the present invention to the lung sections of guinea pigs sensitized with ovalbumin as an antigen.
The amount of SRS-A released was determined by Brocklehurst (J. Physiol., vol. 151, p. 416).
435, 1960). the result,
As shown in Table 2, the compound of the present invention exhibited an extremely strong SRS-A production inhibitory effect at low concentrations.
【表】【table】
【表】
本発明の化合物（）は降圧作用、組織代謝賦
活作用、免疫調整作用、リソゾーム膜安定化作
用、SRS−Ａ産生抑制作用を有し、人間を含む哺
乳動物に対してたとえば不全治療剤、脳循環障害
治療剤、免疫調整剤、抗アレルギー剤（たとえば
喘息、鼻炎の治療剤）などとして用いられる。剤
型としては、たとえばカプセル剤、顆粒剤、散
剤、錠剤、トローチ剤、丸剤、シロツプ剤、注射
剤、坐剤などがあげられるが、抗アレルギー剤と
しては、軟膏剤、エアロゾル剤、吸入剤などとし
て用いることもできる。
また医薬として許容され得る製剤組成物に使用
されるものとしては、例えば白糖、乳糖、ブドウ
糖、でん粉、マンニツト、ソルビツト、セルロー
ス、タルク、シクロデキストリン等の賦形剤、セ
ルロース、メチルセルロース、ポリビニルピロリ
ドン、ゼラチン、アラビヤゴム、ポリエチレング
リコール、白糖、でん粉等の結合剤、でん粉、カ
ルボキシメチルセルロース、カルボキシメチルセ
ルロースのカルシウム塩等の崩壊剤、タルク等の
滑沢剤、矯味剤、安息香酸ナトリウム等の保存
剤、メチルセルロース、ポリビニルピロリドン、
ステアリン酸アルミニウム等のけんだく化剤、ポ
リソルベート80、エマルゲン408、エマゾール310
等の分散剤、水等の溶剤、カカオ脂、ポリエチレ
ングリコール、ウエテプソール、白色ワセリン等
の基剤等が挙げられ、これらは製剤の種類に応じ
て適宜選択される。
本発明の化合物（）は経口もしくは非経口の
ルートにより、成人１日当り５−500mg（0.1−10
mg／Kg）が好んで用いられる。
実施例 １
２，３−ジメトキシ−５−メチル−１，４−ベ
ンゾキノン1.7ｇを酢酸20mlに溶かし、90℃でか
きまぜながらビス−13−メトキシカルボニルトリ
デカノイルパーオキシド7.6ｇを少量ずつ加える。
22時間加熱し、冷後水で希釈しエーテルで抽出す
る。抽出液を飽和食塩水、重ソウ水、食塩水で順
次洗い乾燥する。溶媒を減圧下留去し、残留物を
ヘキサンから再結晶して橙色針状晶の２，３−ジ
メトキシ−６−（12−メトキシカルボニルドデシ
ル）−５−メチル−１，４−ベンゾキノン（：
ｎ＝12、Ｒ＝CH3）1.37ｇを得る。融点54℃。
元素分析 C23H36O6として
計算値 Ｃ、67.62；Ｈ、8.88
実測値 Ｃ、67.52；Ｈ、8.59
実施例 ２
２，３−ジメトキシ−６−（12−メトキシカル
ボニルドデシル）−５−メチル−１，４−ベンゾ
キノン（：ｎ＝12、Ｒ＝CH3）1.5ｇをエーテ
ル200mlに溶かし、20％ハイドロサルフアイトナ
トリウム水溶液75mlと振りまぜる。エーテル層を
分取し、濃縮する。残留物に氷冷下、窒素気流中
30％ハイドロサルフアイトナトリウム水溶液５ml
および30％水酸化カリウム水溶液3.5mlを加える。
反応液を50℃に2.5時間加温する。冷後冷希塩酸
で酸性とし、エーテルで抽出する。エーテルを減
圧下留去し、残留物をメタノール75mlに溶かし、
塩化第二鉄15ｇを水60mlに溶かした溶液を加えて
室温で１時間かきまぜる。反応液を水で希釈し酢
酸エチルで抽出する。抽出液を水洗し、乾燥後溶
媒を減圧下留去する。残留物をエーテル−ヘキサ
ンから結晶化して橙色結晶の６−（12−カルボキ
シドデシル）−２，３−ジメトキシ−５−メチル
−１，４−ベンゾキノン（：ｎ＝12、Ｒ＝Ｈ）
1.09ｇを得る。融点62℃。
元素分析 C22H34O6として
計算値 Ｃ、66.98；Ｈ、8.69
実測値 Ｃ、67.15；Ｈ、8.77
実施例 ３
22−（２−ヒドロキシ−３，４−ジメトキシ−
６−メチルフエニル）ドコサン酸（：ｎ＝21、
Ｒ＝Ｈ）300mgのＮ，Ｎ−ジメチルホルムアミド
20ml溶液にビス（サリシリデン）エチレンジイミ
ノコバルト（）50mgを加え、酸素気流中室温で
24時間かきまぜる。不溶物をろ去し、ろ液を減圧
下濃縮する。残留物を酢酸エチルに溶かし、水
洗、乾燥後溶媒を減圧下留去する。残留物をクロ
ロホルムに溶かしシリカゲルカラムクロマトグラ
フイーに付す。クロロホルムで溶出し、エタノー
ルから再結晶して橙黄色針状の６−（21−カルボ
キシヘンエイコシル）−３，４−ジメトキシ−５
−メチル−１，４−ベンゾキノン（：ｎ＝21、
Ｒ＝Ｈ）を得る。融点86−87℃。
元素分析 C31H52O6として
計算値 Ｃ、71.50；Ｈ、10.07
実測値 Ｃ、71.56；Ｈ、10.06
実施例 ４
６−（18−ヒドロキシオクタデシル）−２，３−
ジメトキシ−５−メチル−１，４−ベンゾキノン
（：ｎ＝17）172mgをアセトン10mlに溶かし、無
水クロム酸2.672ｇを濃硫酸2.3mlに溶かし水で希
釈して10mlとして調整した溶液0.5mlを加え氷冷
下10分間かきまぜる。反応液を水で希釈しクロロ
ホルムで抽出する。抽出液を水洗、乾燥後溶媒を
減圧下留去し、残留物をシリカゲルカラムクロマ
トグラフイーに付す。クロロホルムで溶出し、エ
タノールより再結晶して橙黄色結晶の６−（17−
カルボキシヘプタデシル）−２，３−ジメトキシ
−５−メチル−１，４−ベンゾキノン（：ｎ＝
17、Ｒ＝Ｈ）65mgを得る。融点77−79℃
元素分析 C27H44O6として
計算値 Ｃ、69.79；Ｈ、9.55
実測値 Ｃ、69.86；Ｈ、9.78
実施例 ５
６−（11−ヒドロキシウンデシル）−２，３−ジ
メトキシ−５−メチル−１，４−ベンゾキノン
（：ｎ＝10）を実施例４と同様に反応し、生成
物をシリカゲルクロマトグラフイーで精製して橙
黄色針状晶の６−（10−カルボキシデシル）−２，
３−ジメトキシ−５−メチル−１，４−ベンゾキ
ノン（：ｎ＝10、Ｒ＝Ｈ）を得る。融点50〜52
℃
核磁気共鳴スペクトル（重クロロホルム中のδ
値）：1.32（16H、ｂ、CH2）、2.03（3H、ｓ、
CH3）、2.18−2.65（4H、ｍ、CH2COO、CH2
on the ring）、4.02（6H、ｓ、OCH3）、5.35
（1H、ｂ、COOH）。
実施例 ６
16−（２−ヒドロキシ−３，４−ジメトキシ−
６−メチルフエニル）ヘキサデカン酸（：ｎ＝
15、Ｒ＝Ｈ）（844mg）をジメチルホルムアミド
（20ml）に溶解する。ビス（サリシリデン）エチ
レンジイミノコバルト（）163mgを加え酸素気
流下に室温で24時間撹拌する。溶媒を留去、残留
物を酢酸エチル（100ml）に溶かし、不溶物をろ
去する。母液を1N塩酸と水で洗浄し、無水硫酸
ナトリウムで乾燥する。溶媒を留去し、残留物を
少量のクロロホルムに溶かしシリカゲル（20ｇ）
を担体とするクロマトグラフイーに付し、精製す
る。クロロホルムで展開し、目的物を含む分画を
集め溶媒を留去する。エーテル−石油エーテルか
ら再結晶して、６−（15−カルボキシペンタデシ
ル）−２，３−ジメトキシ−５−メチル−１，４
−ベンゾキノン（：ｎ＝15、Ｒ＝Ｈ）514mgを
得る。融点70−71℃。
元素分析 C25H40O6として
計算値 Ｃ、68.77；Ｈ、9.23
実測値 Ｃ、68.89；Ｈ、9.30
参考例 １
メチル 13−クロロホルミルトリデカノアート
11.7ｇを石油エーテル200mlに溶かし、氷冷下、
かきまぜながら氷水60mlを加えついで過酸化ナト
リウム5.2ｇを少量ずつ加える。１時間かきまぜ
たのちエーテルで抽出する。抽出液を水洗、塩化
カルシウムで乾燥後減圧下溶媒を留去しビス−13
−メトキシカルボニルトリデカノイルパーオキシ
ドの粗結晶7.6ｇを得る。本品は精製することな
く次の工程に付す。赤外吸収スペクトルνfilm naxcm
-1：1790、1760[Table] The compound () of the present invention has antihypertensive action, tissue metabolism activation action, immunomodulation action, lysosomal membrane stabilization action, and SRS-A production inhibitory action, and is a therapeutic agent for mammals including humans. It is used as a therapeutic agent for cerebral circulation disorders, an immunomodulator, an antiallergic agent (for example, a therapeutic agent for asthma and rhinitis), etc. Examples of dosage forms include capsules, granules, powders, tablets, troches, pills, syrups, injections, and suppositories, while antiallergic agents include ointments, aerosols, and inhalers. It can also be used as Examples of substances used in pharmaceutically acceptable pharmaceutical compositions include excipients such as sucrose, lactose, glucose, starch, mannitrate, sorbitol, cellulose, talc, and cyclodextrin, cellulose, methylcellulose, polyvinylpyrrolidone, and gelatin. , binders such as gum arabic, polyethylene glycol, white sugar, starch, disintegrants such as starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose, lubricants such as talc, flavoring agents, preservatives such as sodium benzoate, methylcellulose, polyvinyl pyrrolidone,
Suspension agents such as aluminum stearate, polysorbate 80, Emulgen 408, Emazol 310
and the like, solvents such as water, bases such as cacao butter, polyethylene glycol, wetepsol, and white petrolatum, etc., and these are appropriately selected depending on the type of formulation. The compound of the present invention () can be administered by oral or parenteral route at a dosage of 5-500 mg (0.1-10 mg) per day for adults.
mg/Kg) is preferably used. Example 1 1.7 g of 2,3-dimethoxy-5-methyl-1,4-benzoquinone is dissolved in 20 ml of acetic acid, and 7.6 g of bis-13-methoxycarbonyltridecanoyl peroxide is added little by little while stirring at 90°C.
Heat for 22 hours, cool, dilute with water and extract with ether. The extract is sequentially washed with saturated saline, diluted sodium chloride solution, and saline, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to give orange needle-like crystals of 2,3-dimethoxy-6-(12-methoxycarbonyldodecyl)-5-methyl-1,4-benzoquinone (:
n=12, R=CH 3 ) 1.37 g are obtained. Melting point 54℃. Elemental analysis As C 23 H 36 O 6 Calculated value C, 67.62; H, 8.88 Actual value C, 67.52; H, 8.59 Example 2 2,3-dimethoxy-6-(12-methoxycarbonyldodecyl)-5-methyl- 1.5 g of 1,4-benzoquinone (n=12, R=CH 3 ) is dissolved in 200 ml of ether and mixed with 75 ml of 20% sodium hydrosulfite aqueous solution. Separate the ether layer and concentrate. The residue is cooled on ice and in a nitrogen stream.
30% sodium hydrosulfite aqueous solution 5ml
and 3.5 ml of 30% potassium hydroxide aqueous solution.
Warm the reaction to 50°C for 2.5 hours. After cooling, acidify with cold dilute hydrochloric acid and extract with ether. The ether was distilled off under reduced pressure, and the residue was dissolved in 75 ml of methanol.
Add a solution of 15 g of ferric chloride dissolved in 60 ml of water and stir at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was crystallized from ether-hexane to give orange crystals of 6-(12-carboxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (n=12, R=H).
Obtain 1.09g. Melting point 62℃. Elemental analysis As C 22 H 34 O 6 Calculated value C, 66.98; H, 8.69 Actual value C, 67.15; H, 8.77 Example 3 22-(2-hydroxy-3,4-dimethoxy-
6-methylphenyl) docosanoic acid (:n=21,
R=H) 300 mg N,N-dimethylformamide
Add 50 mg of bis(salicylidene) ethylenediiminocobalt () to 20 ml of solution and incubate at room temperature in an oxygen stream.
Stir for 24 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and subjected to silica gel column chromatography. Elution with chloroform and recrystallization from ethanol yielded orange-yellow needles of 6-(21-carboxyheneicosyl)-3,4-dimethoxy-5.
-Methyl-1,4-benzoquinone (:n=21,
R=H) is obtained. Melting point 86-87℃. Elemental analysis As C 31 H 52 O 6 Calculated value C, 71.50; H, 10.07 Actual value C, 71.56; H, 10.06 Example 4 6-(18-hydroxyoctadecyl)-2,3-
Dissolve 172 mg of dimethoxy-5-methyl-1,4-benzoquinone (: n = 17) in 10 ml of acetone, add 0.5 ml of a solution prepared by dissolving 2.672 g of chromic anhydride in 2.3 ml of concentrated sulfuric acid and diluting with water to make 10 ml. Stir on ice for 10 minutes. The reaction solution was diluted with water and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Elution with chloroform and recrystallization from ethanol yielded orange-yellow crystals of 6-(17-
carboxyheptadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (:n=
17, R=H) to obtain 65 mg. Melting point 77-79℃ Elemental analysis As C 27 H 44 O 6 Calculated value C, 69.79; H, 9.55 Actual value C, 69.86; H, 9.78 Example 5 6-(11-hydroxyundecyl)-2,3-dimethoxy -5-Methyl-1,4-benzoquinone (n=10) was reacted in the same manner as in Example 4, and the product was purified by silica gel chromatography to form orange-yellow needles of 6-(10-carboxydecyl). )-2,
3-dimethoxy-5-methyl-1,4-benzoquinone (:n=10, R=H) is obtained. Melting point 50-52
°C Nuclear magnetic resonance spectrum (δ in deuterated chloroform
Value): 1.32 (16H, b, CH 2 ), 2.03 (3H, s,
CH 3 ), 2.18−2.65 (4H, m, CH 2 COO, CH 2
on the ring), 4.02 (6H, s, OCH 3 ), 5.35
(1H, b, COOH). Example 6 16-(2-hydroxy-3,4-dimethoxy-
6-methylphenyl)hexadecanoic acid (:n=
15, R=H) (844 mg) is dissolved in dimethylformamide (20 ml). Add 163 mg of bis(salicylidene)ethylenediiminocobalt () and stir at room temperature for 24 hours under an oxygen stream. The solvent was distilled off, the residue was dissolved in ethyl acetate (100 ml), and the insoluble matter was filtered off. Wash the mother liquor with 1N hydrochloric acid and water and dry over anhydrous sodium sulfate. The solvent was distilled off and the residue was dissolved in a small amount of chloroform and silica gel (20g)
Purify by subjecting it to chromatography using as a carrier. Develop with chloroform, collect fractions containing the target product, and evaporate the solvent. Recrystallization from ether-petroleum ether gave 6-(15-carboxypentadecyl)-2,3-dimethoxy-5-methyl-1,4
-514 mg of benzoquinone (:n=15, R=H) are obtained. Melting point 70-71℃. Elemental analysis As C 25 H 40 O 6 Calculated value C, 68.77; H, 9.23 Actual value C, 68.89; H, 9.30 Reference example 1 Methyl 13-chloroformyl tridecanoate
Dissolve 11.7g in 200ml of petroleum ether and cool on ice.
Add 60 ml of ice water while stirring, and then add 5.2 g of sodium peroxide little by little. After stirring for 1 hour, extract with ether. After washing the extract with water and drying with calcium chloride, the solvent was distilled off under reduced pressure and Bis-13
- 7.6 g of crude crystals of methoxycarbonyl tridecanoyl peroxide are obtained. This product can be submitted to the next process without being purified. Infrared absorption spectrum ν film nax cm
-1 : 1790, 1760
【式】1730
（COOCH3）。
参考例 ２
11−アセトキシ−ｎ−ウンデシル酸クロリド
（27.6ｇ）の１，２−ジクロルエタン溶液（150
ml）に塩化アルミニウム（28ｇ）を加え、室温で
２時間かき混ぜる。本反応液を５℃に冷却し、こ
れに３，４，５−トリメトキシトルエン（19.1
ｇ）の１，２−ジクロルエタン溶液（50ml）を加
え、室温で72時間かき混ぜる。ついで反応液を50
−60℃に加熱し、さらに30分間かきまぜる。放冷
後反応液に氷水300mlを加え生成物をジクロルメ
タンで抽出する。ジクロルメタン層は水洗し、無
水硫酸マグネシウムで乾燥後、溶媒を留去すると
淡黄色油状物として６−（11−アセトキシ−１−
オキソウンデシル）−２，３−ジメトキシ−５−
メチルフエノール（35ｇ）が得られる。
IRνNeat naxcm-1：1730（OAc）、1680（Co）、1610、
1580（Ar）
MS ｍ／ｅ：394（M+）、352、334、195
６−（11−アセトキシ−１−オキソウンデシル）
−２，３−ジメトキシ−５−メチルフエノール
（34ｇ）のメタノール溶液（300ml）に水酸化ナト
リウム（７ｇ）を加え、室温で２時間かき混ぜ
る。反応液を5N塩酸を加え中和した後、溶媒を
留去すると粗結晶が得られる。本品を水洗し、つ
いでエーテル−ヘキサン（１：１）から再結晶す
ると無色針状晶の６−（11−ヒドロキシ−１−オ
キソウンデシル）−２，３−ジメトキシ−５−メ
チルフエノール（30ｇ）が得られる。融点81℃
元素分析 C20H32O5として
計算値 Ｃ、68.15；Ｈ、9.15
実測値 Ｃ、68.47；Ｈ、9.30
６−（11−ヒドロキシ−１−オキソウンデシル）
−２，３−ジメトキシ−５−メチルフエノール
（14ｇ）の酢酸溶液（200ml）に５％パラジウムカ
ーボン（50％含水物）（３ｇ）と70％過塩素酸
（0.1ml）を加え、常温、常圧で接触還元する。水
素の吸収が終了したら触媒を別し、液を減圧
下に濃縮する。残留物をジクロルメタンで抽出
し、ジクロルメタン層は５％炭酸水素ナトリウム
水溶液で洗浄後、無水硫酸マグネシウムで乾燥す
る。溶媒を留去すると無色油状物として６−（11
−アセトキシウンデシル）−２，３−ジメトキシ
−５−メチルフエノール（15ｇ）が得られる。
IRνNeat naxcm-1：3450（OH）、1730（OAc）、1610、
1580（Ar）
NMRδCDCl3 ppn：1.1−1.9〔18H、ｍ、−（CH2）9−〕、
2.02（3H、ｓ、OAc）、2.22（3H、ｓ、C5−
CH3）、2.54（2H、ｔ、Ｊ＝７Hz、C1′−H2）、
3.79（3H、ｓ、OCH3）、3.83（3H、ｓ、
OCH3）、4.01（2H、ｔ、Ｊ＝６Hz、−CH2
OAc）、5.78（1H、ｓ、C1−OH）、6.23（1H、
ｓ、C4−Ｈ）
MS ｍ／ｅ：380（M+）、338、181
６−（11−アセトキシウンデシル）−２，３−ジ
メトキシ−５−メチルフエノール（８ｇ）のＮ，
Ｎ−ジメチルホルムアミド溶液（400ml）にニト
ロソジスルホン酸カリウム（24ｇ）、水（400ml）、
メタノール（30ml）およびリン酸一カリウム
（1.0ｇ）を加え、室温で28日間かき混ぜる。生成
物をジクロルメタンで抽出し、ジクロルメタン層
は水洗し、無水硫酸マグネシウムで乾燥する。溶
媒を留去すると粗結晶が得られる。ヘキサンから
再結晶すると橙黄色針状晶の６−（11−アセトキ
シウンデシル）−２，３−ジメトキシ−５−メチ
ル−１，４−ベンゾキノン（6.4ｇ）が得られる。
融点41℃
元素分析 C22H34O6として
計算値 Ｃ、66.98；Ｈ、8.69
実測値 Ｃ、66.98；Ｈ、8.86
６−（11−アセトキシウンデシル）−２，３−ジ
メトキシ−５−メチル−１，４−ベンゾキノン
（4.2ｇ）のメタノール溶液（200ml）に濃塩酸
（0.1ml）を加え、室温で12時間放置する。反応液
に炭酸水素ナトリウム（0.2ｇ）を加え、溶媒を
留去する。生成物をジクロルメタンに溶解し、不
溶物を別する。ジクロルメタンを留去すると粗
結晶が得られる。ヘキサン−エーテル（３：１）
から再結晶すると橙黄色針状晶の６−（11−ヒド
ロキシウンデシル）−２，３−ジメトキシ−５−
メチル−１，４−ベンゾキノン（：ｎ＝10）
（3.6ｇ）が得られる。融点57℃。
元素分析 C20H32O5として
計算値 Ｃ、68.15；Ｈ、9.15
実測値 Ｃ、68.22；Ｈ、9.19
参考例 ３
18−アセトキシ−ｎ−オクタデカン酸クロリド
（11ｇ）の１，２−ジクロルエタン溶液（50ml）
に塩化アルミニウム（７ｇ）を加え、室温で２時
間かき混ぜる。本反応液を５℃に冷却し、これに
３，４，５−トリメトキシトルエン（6.2ｇ）の
１，２−ジクロルエタン溶液（20ml）を加え、室
温で72時間かき混ぜる。ついで反応液を50゜−60
℃に加温して30分間かき混ぜる。放冷後反応液に
氷水を加え、生成物をジクロルメタンで抽出す
る。ジクロルメタン層は水洗してから溶媒を留去
すると油状物（12.1ｇ）が得られる。本品をメタ
ノール（150ml）に溶解し、これに水酸化ナトリ
ウム（5.2ｇ）を加え、室温で２時間かき混ぜる。
反応液を5N塩酸で中和し、溶媒を留去すると粗
結晶が析出する。本品を水洗した後、ジクロルメ
タン−エーテル（１：１）から再結晶すると無色
針状晶の６−（18−ヒドロキシ−１−オキソオク
タデシル）−２，３−ジメトキシ−５−メチルフ
エノール（6.4ｇ）が得られる。融点101℃
元素分析 C27H46O5として
計算値 Ｃ、71.96；Ｈ、10.29
実測値 Ｃ、72.08；Ｈ、10.51
６−（18−ヒドロキシ−１−オキソオクタデシ
ル）−２，３−ジメトキシ−５−メチルフエノー
ル（1.4ｇ）酢酸溶液（30ml）に５％パラジウム
カーボン（50％含水物）（0.5ｇ）と70％過塩素酸
（0.05ml）を加え常温、常圧で接触還元する。水
素の吸収が終了したら、触媒を別し、液を減
圧下に濃縮すると無色油状物が得られる。本品を
エーテルに溶解しエーテル層は５％炭酸水素ナト
リウム水溶液で洗浄後、無水硫酸ナトリウムで乾
燥後、溶媒を留去すると粗結晶が得られる。ヘキ
サンから再結晶すると無色針状晶の６−（18−ア
セトキシオクタデシル）−２，３−ジメトキシ−
５−メチルフエノール（1.4ｇ）が得られる。融
点53℃
元素分析 C29H50O5として
計算値 Ｃ、72.76；Ｈ、10.53
実測値 Ｃ、73.05；Ｈ、10.31
上記18−アセトキシ体から参考例２の該工程に
示した方法で脱アセチル化して得られる６−（18
−ヒドロキシオクタデシル）−２，３−ジメトキ
シ−５−メチルフエノール（0.5ｇ）のジメチル
ホルムアミド溶液（１）に、ニトロソジスルホ
ン酸カリウム（13ｇ）、水700ml、メタノール100
mlおよびリン酸一カリウム（１ｇ）を加え、室温
で45日間かき混ぜる。生成物は常法に従つて抽出
し、エーテル−ヘキサンから再結晶すると黄色針
状晶の６−（18−ヒドロキシオクタデシル）−２，
３−ジメトキシ−５−メチル−１，４−ベンゾキ
ノン（、ｎ＝17）（0.31ｇ）が得られる。融点
81℃
元素分析 C27H46O5として
計算値 Ｃ、71.96；Ｈ、10.29
実測値 Ｃ、72.06；Ｈ、10.27
参考例 ４
１，20−エイコサンジカルボン酸モノメチルエ
ステル１ｇを塩化チオニル５mlに溶かし室温で12
時間かき混ぜたのち減圧下過剰の塩化チオニルを
留去しメチル21−クロロホルミルヘンエイコサノ
アートの粗結晶を得る。本品は精製することなく
次の工程に付す。赤外吸収スペクトル
νKBr naxcm-1：1790（COCl）、1730（COOCH3）
メチル21−クロロホルミルヘンエイコサノアー
ト８ｇを１，２−ジクロロエタン60mlに溶かし、
塩化アルミニウム5.5ｇを加えかきまぜる。氷冷
下かきまぜながら窒素気流中３，４，５−トリメ
トキシトルエン5.67ｇの１，２−ジクロルエタン
（13ml）溶液を滴下し、48時間かきまぜる。つい
で塩化アルミニウム1.3ｇを加え室温で16時間、
さらに35〜38℃で40分間かきまぜる。反応後に氷
水および3N塩酸を加えクロロホルムで抽出する。
抽出後を順次水、飽和炭酸水素ナトリウム水溶
液、水で洗い乾燥する。溶媒を減圧下留去し、残
留物をシリカゲルクロマトグラフイーに付す。目
的物の画分を集めメタノールから再結晶して無色
針状晶のメチル21−（２−ヒドロキシ−３，４−
ジメトキシ−６−メチルベンゾイル）ヘンエイコ
サノアートを得る。融点73〜74℃。核磁気共鳴ス
ペクトル（重クロロホルム中のδ値）：1.24、
（36H、ｂ、CH2）、２，27（2H、ｔ、CH2COO）、
2.42（3H、ｓ、核CH3）、2.86（2H、ｔ、
COCH2）、3.64（3H、ｓ、COOCH3）、3.84（3H、
ｓ、OCH3）、3.87（3H、ｓ、OCH3）、6.22（1H、
ｓ、核Ｈ）
メチル21−（２−ヒドロキシ−３，４−ジメト
キシ−６−メチルベンゾイル）ヘンエイコサノア
ートの酢酸溶液に過塩素酸を加え５％パラジウム
−炭素を用い接触還元に付す。参考例２の該工程
と同様に処理して得られる生成物をエタノールか
ら再結晶して無色針状晶のメチル22−（２−ヒド
ロキシ−３，４−ジメトキシ−６−メチルフエニ
ル）ドコサノアートを得る。融点71−72.5℃
元素分析 C32H56O5として
計算値 Ｃ、73.80；Ｈ、10.84
実測値 Ｃ、74.06；Ｈ、11.06
メチル22−（２−ヒドロキシ−３，４−ジメト
キシ−６−メチルフエニル）ドコサノアート300
mgをメタノール15mlに溶かし、14％水酸化ナトリ
ム水溶液20mlを加え50〜60℃で1.5時間かきまぜ
る。反応液を3N塩酸で酸性とし酢酸エチルで抽
出する。抽出液を水洗、乾燥後減圧下溶媒を留去
する。残留物をメタノールから再結晶して22−
（２−ヒドロキシ−３，４−ジメトキシ−６−メ
チルフエニル）ドコサン酸（：ｎ＝21）を得
る。融点67−68℃。
核磁気共鳴スペクトル（重クロロホルム中のδ
値）：１，27（38H、ｂ、CH2）、2.24（3H、ｓ、
核CH3）、2.28−2.56（4H、ｍ、CH2COO、核
CH2）、3.80（3H、ｓ、OCH3）、3.84（3H、ｓ、
OCH3）、6.24（1H、ｓ、核Ｈ）
参考例 ５
10−（２−ヒドロキシ−３，４−ジメトキシ−
６−メチルフエニル）デカン酸（33.8ｇ）を無水
酢酸（100ml）に懸濁し、濃硫酸（５ml）を加え
る。室温で1.5時間反応させる。溶媒を留去し、
残留物にジオキサン（250ml）−５％炭酸水素ナト
リウム水溶液（250ml）を加え、室温で24時間撹
拌する。6N塩酸でPH３としここに酢酸エチル
（300ml）と水（500ml）を加えて抽出する。酢酸
エチル層を水洗し、硫酸ナトリウムで乾燥する。
溶媒を留去して油状の10−（２−アセトキシ−３，
４−ジメトキシ−６−メチルフエニル）デカン酸
36.2ｇを得る。このものを無水ベンゼン（50ml）
に溶かし、氷冷下にオキザリルクロリド（25ml）
を滴下する。滴下後発泡がおさまつた後に、50℃
にて１時間反応させる。溶媒を留去し、トルエン
を加えさらに減圧下溶媒を留去する。水酸化ナト
リウムを入れたデシケーター中で乾燥し、６−
（９−クロロホルミルノニル）−２，３−ジメトキ
シ−５−メチルフエニルアセタート36.9ｇを得
る。核磁気共鳴スペクトル（重クロロホルム中の
δ値）：1.33（14H、ｂ、CH2）、2.33、2.37（6H、
ｓ、COCH3、核CH3）、2.95（4H、ｔ、CH2CO、
核CH2）、3.87、3.90（6H、ｓ、OCH3）、6.73
（1H、ｓ、核Ｈ）。赤外吸収スペクトルνfilm naxcm
-1：1800（COCl）、1770（OCOCH3）。
６−（９−クロロホルミルノニル）−２，３−ジ
メトキシ−５−メチルフエニルアセタート（5.0
ｇ）をクロロホルム（４ml）に溶かした溶液を、
氷冷下に１−モルホリノ−１−シクロヘキセン
（2.51ｇ）とトリエチルアミン（1.93ml）の混合
物に滴下する。滴下後、室温で90時間反応させ
る。反応液に6N塩酸（7.5ml）を加え激しく撹拌
しながら５時間加熱還元させる。クロロホルム
（20ml）−水（20ml）を追加し抽出する。水層をさ
らにクロロホルム（20ml）で抽出し、クロロホル
ム層を合わせ、水洗、無水硫酸ナトリウムで乾燥
する。溶媒を留去し、残留物を再びクロロホルム
に溶かしシリカゲル（60ｇ）を担体とするクロマ
トグラフイーに付す。クロロホルムで展開し、目
的物を含む分画を集め溶媒を留去して油状の２−
｛10−（２−アセトキシ−３，４−ジメトキシ−６
−メチルフエニル）デカノイル｝シクロヘキサノ
ン3.2ｇを得る。このものをエタノール（3.5ml）
に溶かし、熱した6N水酸化ナトリウム水溶液
（3.5ml）に加え、10分間加熱還流させる。室温に
戻したのち、6N塩酸を加えてPH２とし、ここに
酢酸エチル（30ml）と水（30ml）を加えて抽出す
る。水層をさらに酢酸エチル（10ml）で抽出し、
酢酸エチル層を合わせて水洗、無水硫酸ナトリウ
ムで乾燥する。溶媒を留去し残留物をエーテル−
石油エーテルから再結晶して７−オキソ−16−
（２−ヒドロキシ−３，４−ジメトキシ−６−メ
チルフエニル）ヘキサデカン酸1.96ｇを得る。融
点55−57℃。
元素分析 C25H40O6として
計算値 Ｃ、68.77；Ｈ、9.73
実測値 Ｃ、68.64；Ｈ、9.40
ｐ−トルエンスルホン酸（100mg）を含むジメ
チルホルムアミド（10ml）−スルホラン（10ml）
の混合溶媒に、７−オキソ−16−（２−ヒドロキ
シ−３，４−ジメトキシ−６−メチルフエニル）
ヘキサデカン酸（1.75ｇ）とｐ−トルエンスルホ
ニルヒドラジド（930mg）を100℃で加える。５分
後にシクロヘキサン（10ml）と水素化シアノホウ
素ナトリウム（1.0ｇ）を加える。100℃で20分間
反応させる。室温にまで戻した後、飽和食塩水
（100ml）を加えエーテル（50ml×２回）で抽出す
る。エーテル層を合わせ、水、1N塩酸、再び水
で洗浄し、無水硫酸ナトリウムで乾燥する。溶媒
を留去し、残渣をクロロホルムに溶かし、シリカ
ゲルカラムクロマトグラフイーに付す。クロロホ
ルムで溶出し、目的物を含む分画を集め溶媒を留
去する。残留物の結晶に石油エーテルを加え、冷
却後にろ取する。16−（２−ヒドロキシ−３，４
−ジメトキシ−６−メチルフエニル）ヘキサデカ
ン酸970mgを得る。融点45−46℃。
元素分析 C25H42O5として
計算値 Ｃ、71.05；Ｈ、10.02
実測値 Ｃ、71.13；Ｈ、10.13
参考例 ６
(1) ６−（９−クロロホルミルノニル）−２，３−
ジメトキシ−５−メチルフエニルアセタート
（36.9ｇ）と１−モルホリノ−１−シクロドデ
セン（24.3ｇ）をトリエチルアミン（14.3ml）
の存在下に参考例５の該工程と同様に反応させ
る。反応物を6N塩酸（47ml）で処理し、得ら
れた２−｛10−（２−アセトキシ−３，４−ジメ
トキシ−６−メチルフエニル）デカノイル｝シ
クロドデカノン（46.3ｇ）を6N水酸化ナトリ
ウム水溶液で加水分解して13−オキソ−22−
（２−ヒドロキシ−３，４−ジメトキシ−６−
メチルフエニル）ドコサン酸32.4ｇを得る。融
点63−64℃。
元素分析 C31H52O6として
計算値 Ｃ、71.50；Ｈ、10.07
実測値 Ｃ、71.57；Ｈ、10.17
(2) 13−オキソ−22−（２−ヒドロキシ−３，４
−ジメトキシ−６−メチルフエニル）ドコサン
酸（5.21ｇ）をｐ−トルエンスルホン酸（250
mg）とｐ−トルエンスルホニルヒドラジド
（2.33ｇ）の存在下に、ジメチルホルムアミド
（25ml）−スルホラン（25ml）−シクロヘキサン
（25ml）の混合溶媒中で参考例５の該工程と同
様にして還元して得られる粗製物をメタノール
から再結晶して22−（２−ヒドロキシ−３，４
−ジメトキシ−６−メチルフエニル）ドコサン
酸2.97ｇを得る。融点67−68℃。本品は参考例
４で得た結晶と物理化学定数がすべて一致し
た。
元素分析 C31H54O5として
計算値 Ｃ、73.47；Ｈ、10.74
実測値 Ｃ、73.76；Ｈ、10.08[Formula] 1730 (COOCH 3 ). Reference Example 2 A solution of 11-acetoxy-n-undecylic acid chloride (27.6 g) in 1,2-dichloroethane (150
ml) and add aluminum chloride (28 g) to the mixture and stir at room temperature for 2 hours. This reaction solution was cooled to 5°C, and 3,4,5-trimethoxytoluene (19.1
Add a 1,2-dichloroethane solution (50 ml) of g) and stir at room temperature for 72 hours. Then add 50% of the reaction solution.
Heat to -60°C and stir for an additional 30 minutes. After cooling, add 300 ml of ice water to the reaction solution and extract the product with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 6-(11-acetoxy-1-
oxoundecyl)-2,3-dimethoxy-5-
Methylphenol (35 g) is obtained. IRν Neat nax cm -1 : 1730 (OAc), 1680 (Co), 1610,
1580 (Ar) MS m/e: 394 (M + ), 352, 334, 195 6-(11-acetoxy-1-oxoundecyl)
Add sodium hydroxide (7 g) to a methanol solution (300 ml) of -2,3-dimethoxy-5-methylphenol (34 g) and stir at room temperature for 2 hours. After neutralizing the reaction solution by adding 5N hydrochloric acid, the solvent is distilled off to obtain crude crystals. When this product was washed with water and then recrystallized from ether-hexane (1:1), 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (30 g) was obtained as colorless needle-like crystals. can get. Melting point 81℃ Elemental analysis C 20 H 32 O 5 Calculated value C, 68.15; H, 9.15 Actual value C, 68.47; H, 9.30 6-(11-hydroxy-1-oxoundecyl)
Add 5% palladium carbon (50% hydrate) (3 g) and 70% perchloric acid (0.1 ml) to an acetic acid solution (200 ml) of -2,3-dimethoxy-5-methylphenol (14 g), and leave it at room temperature. Catalytic reduction under pressure. When hydrogen absorption is completed, the catalyst is separated and the liquid is concentrated under reduced pressure. The residue is extracted with dichloromethane, and the dichloromethane layer is washed with a 5% aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. When the solvent was distilled off, 6-(11
-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (15 g) is obtained. IRν Neat nax cm -1 : 3450 (OH), 1730 (OAc), 1610,
1580(Ar) NMRδ CDCl3 ppn : 1.1−1.9 [18H, m, −(CH 2 ) 9 −],
2.02 (3H, s, OAc), 2.22 (3H, s, C 5 −
CH3 ), 2.54 (2H, t, J=7Hz, C1' - H2 ),
3.79 (3H, s, OCH 3 ), 3.83 (3H, s,
OCH 3 ), 4.01 (2H, t, J=6Hz, -CH 2
OAc), 5.78 (1H, s, C 1 -OH), 6.23 (1H,
MS m/e: 380 (M + ), 338, 181 N of 6-(11-acetoxyundecyl)-2,3-dimethoxy- 5 -methylphenol (8 g),
Potassium nitrosodisulfonate (24 g), water (400 ml), N-dimethylformamide solution (400 ml),
Add methanol (30 ml) and monopotassium phosphate (1.0 g) and stir at room temperature for 28 days. The product is extracted with dichloromethane, and the dichloromethane layer is washed with water and dried over anhydrous magnesium sulfate. When the solvent is distilled off, crude crystals are obtained. Recrystallization from hexane gives 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.4 g) as orange-yellow needles.
Melting point 41℃ Elemental analysis C 22 H 34 O 6 Calculated value C, 66.98; H, 8.69 Actual value C, 66.98; H, 8.86 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl- Concentrated hydrochloric acid (0.1 ml) is added to a methanol solution (200 ml) of 1,4-benzoquinone (4.2 g), and the mixture is left at room temperature for 12 hours. Sodium hydrogen carbonate (0.2 g) was added to the reaction solution, and the solvent was distilled off. The product is dissolved in dichloromethane and the insoluble materials are separated. Dichloromethane is distilled off to obtain crude crystals. Hexane-ether (3:1)
Recrystallization from 6-(11-hydroxyundecyl)-2,3-dimethoxy-5-
Methyl-1,4-benzoquinone (:n=10)
(3.6g) is obtained. Melting point: 57℃. Elemental analysis As C 20 H 32 O 5 Calculated value C, 68.15; H, 9.15 Actual value C, 68.22; H, 9.19 Reference example 3 A solution of 18-acetoxy-n-octadecanoic acid chloride (11 g) in 1,2-dichloroethane ( 50ml)
Add aluminum chloride (7 g) to the mixture and stir at room temperature for 2 hours. The reaction solution was cooled to 5°C, a solution of 3,4,5-trimethoxytoluene (6.2 g) in 1,2-dichloroethane (20 ml) was added, and the mixture was stirred at room temperature for 72 hours. Then, the reaction solution was heated at 50°−60
Warm to ℃ and stir for 30 minutes. After cooling, ice water is added to the reaction mixture, and the product is extracted with dichloromethane. The dichloromethane layer was washed with water and the solvent was distilled off to obtain an oil (12.1 g). Dissolve this product in methanol (150 ml), add sodium hydroxide (5.2 g), and stir at room temperature for 2 hours.
The reaction solution is neutralized with 5N hydrochloric acid, and the solvent is distilled off to precipitate crude crystals. After washing this product with water, it was recrystallized from dichloromethane-ether (1:1) to form colorless needle-like crystals of 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (6.4 g). ) is obtained. Melting point 101℃ Elemental analysis C 27 H 46 O 5 Calculated value C, 71.96; H, 10.29 Actual value C, 72.08; H, 10.51 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5 - Add 5% palladium carbon (50% hydrate) (0.5 g) and 70% perchloric acid (0.05 ml) to a solution of methylphenol (1.4 g) in acetic acid (30 ml) and perform catalytic reduction at room temperature and pressure. After hydrogen absorption is completed, the catalyst is separated and the liquid is concentrated under reduced pressure to obtain a colorless oil. This product is dissolved in ether, the ether layer is washed with a 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain crude crystals. Recrystallization from hexane gives colorless needle-like crystals of 6-(18-acetoxyoctadecyl)-2,3-dimethoxy-
5-methylphenol (1.4 g) is obtained. Melting point 53℃ Elemental analysis C 29 H 50 O 5 Calculated value C, 72.76; H, 10.53 Actual value C, 73.05; H, 10.31 The above 18-acetoxy compound was deacetylated by the method shown in the step of Reference Example 2. 6-(18
-Hydroxyoctadecyl)-2,3-dimethoxy-5-methylphenol (0.5g) in dimethylformamide solution (1), potassium nitrosodisulfonate (13g), water 700ml, methanol 100ml
ml and monopotassium phosphate (1 g) and stir at room temperature for 45 days. The product was extracted in a conventional manner and recrystallized from ether-hexane to give yellow needle-like crystals of 6-(18-hydroxyoctadecyl)-2,
3-dimethoxy-5-methyl-1,4-benzoquinone (n=17) (0.31 g) is obtained. melting point
81℃ Elemental analysis C 27 H 46 O 5 Calculated value C, 71.96; H, 10.29 Actual value C, 72.06; H, 10.27 Reference example 4 Dissolve 1 g of 1,20-eicosandicarboxylic acid monomethyl ester in 5 ml of thionyl chloride and room temperature at 12
After stirring for a period of time, excess thionyl chloride was distilled off under reduced pressure to obtain crude crystals of methyl 21-chloroformylheneicosanoate. This product can be submitted to the next process without being purified. Infrared absorption spectrum ν KBr nax cm -1 : 1790 (COCl), 1730 (COOCH 3 ) 8 g of methyl 21-chloroformylheneicosanoate was dissolved in 60 ml of 1,2-dichloroethane.
Add 5.5 g of aluminum chloride and stir. While stirring under ice-cooling, a solution of 5.67 g of 3,4,5-trimethoxytoluene in 1,2-dichloroethane (13 ml) was added dropwise in a nitrogen stream, and the mixture was stirred for 48 hours. Then, 1.3g of aluminum chloride was added and kept at room temperature for 16 hours.
Stir for another 40 minutes at 35-38°C. After the reaction, ice water and 3N hydrochloric acid are added and extracted with chloroform.
After extraction, the extract is washed successively with water, a saturated aqueous sodium bicarbonate solution, and water, and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. Fractions of the target product were collected and recrystallized from methanol to give colorless needle-like crystals of methyl 21-(2-hydroxy-3,4-
Dimethoxy-6-methylbenzoyl)heneicosanoate is obtained. Melting point 73-74℃. Nuclear magnetic resonance spectrum (δ value in deuterochloroform): 1.24,
(36H, b, CH 2 ), 2,27 (2H, t, CH 2 COO),
2.42 (3H, s, nuclear CH 3 ), 2.86 (2H, t,
COOCH 2 ), 3.64 (3H, s, COOCH 3 ), 3.84 (3H,
s, OCH 3 ), 3.87 (3H, s, OCH 3 ), 6.22 (1H,
s, nucleus H) Perchloric acid is added to an acetic acid solution of methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate, followed by catalytic reduction using 5% palladium on carbon. The product obtained by treatment in the same manner as in this step of Reference Example 2 is recrystallized from ethanol to obtain colorless needle-like crystals of methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate. Melting point 71-72.5℃ Elemental analysis C 32 H 56 O 5 Calculated value C, 73.80; H, 10.84 Actual value C, 74.06; H, 11.06 Methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl) Dokosano Art 300
Dissolve mg in 15 ml of methanol, add 20 ml of 14% sodium hydroxide aqueous solution, and stir at 50 to 60°C for 1.5 hours. The reaction solution was made acidic with 3N hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol and 22−
(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (n=21) is obtained. Melting point 67-68℃. Nuclear magnetic resonance spectrum (δ in deuterated chloroform
Value): 1,27 (38H, b, CH 2 ), 2.24 (3H, s,
nuclear CH 3 ), 2.28−2.56 (4H, m, CH 2 COO, nuclear
CH 2 ), 3.80 (3H, s, OCH 3 ), 3.84 (3H, s,
OCH 3 ), 6.24 (1H, s, nuclear H) Reference example 5 10-(2-hydroxy-3,4-dimethoxy-
6-Methylphenyl)decanoic acid (33.8 g) is suspended in acetic anhydride (100 ml) and concentrated sulfuric acid (5 ml) is added. Incubate for 1.5 hours at room temperature. Distill the solvent,
Dioxane (250 ml) and 5% aqueous sodium hydrogen carbonate solution (250 ml) were added to the residue, and the mixture was stirred at room temperature for 24 hours. Adjust the pH to 3 with 6N hydrochloric acid, add ethyl acetate (300 ml) and water (500 ml), and extract. Wash the ethyl acetate layer with water and dry with sodium sulfate.
The solvent was distilled off to give an oily 10-(2-acetoxy-3,
4-dimethoxy-6-methylphenyl)decanoic acid
Obtain 36.2g. Add this to anhydrous benzene (50ml)
Dissolve oxalyl chloride (25 ml) under ice-cooling.
drip. After the foaming subsides after dropping, heat to 50℃.
Allow to react for 1 hour. The solvent was distilled off, toluene was added, and the solvent was further distilled off under reduced pressure. Dry in a desiccator containing sodium hydroxide, 6-
36.9 g of (9-chloroformylnonyl)-2,3-dimethoxy-5-methylphenylacetate are obtained. Nuclear magnetic resonance spectrum (δ value in deuterated chloroform): 1.33 (14H, b, CH 2 ), 2.33, 2.37 (6H,
s, COCH 3 , nuclear CH 3 ), 2.95 (4H, t, CH 2 CO,
Nuclear CH 2 ), 3.87, 3.90 (6H, s, OCH 3 ), 6.73
(1H, s, nuclear H). Infrared absorption spectrum ν film nax cm
-1 : 1800 (COCl), 1770 (OCOCH 3 ). 6-(9-chloroformylnonyl)-2,3-dimethoxy-5-methylphenylacetate (5.0
g) in chloroform (4 ml),
The mixture was added dropwise to a mixture of 1-morpholino-1-cyclohexene (2.51 g) and triethylamine (1.93 ml) under ice cooling. After dropping, react at room temperature for 90 hours. Add 6N hydrochloric acid (7.5 ml) to the reaction solution, and heat and reduce for 5 hours while stirring vigorously. Add chloroform (20 ml)-water (20 ml) and extract. The aqueous layer is further extracted with chloroform (20 ml), the chloroform layers are combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dissolved again in chloroform and subjected to chromatography using silica gel (60 g) as a carrier. Developed with chloroform, collected fractions containing the target product, and distilled off the solvent to obtain an oily 2-
{10-(2-acetoxy-3,4-dimethoxy-6
3.2 g of -methylphenyl)decanoyl}cyclohexanone are obtained. Add this to ethanol (3.5ml)
Add to heated 6N aqueous sodium hydroxide solution (3.5ml) and heat under reflux for 10 minutes. After returning to room temperature, add 6N hydrochloric acid to adjust the pH to 2, then add ethyl acetate (30 ml) and water (30 ml) for extraction. The aqueous layer was further extracted with ethyl acetate (10ml),
The ethyl acetate layers are combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was dissolved in ether.
Recrystallized from petroleum ether to give 7-oxo-16-
1.96 g of (2-hydroxy-3,4-dimethoxy-6-methylphenyl)hexadecanoic acid are obtained. Melting point 55-57℃. Elemental analysis C 25 H 40 O 6 Calculated value C, 68.77; H, 9.73 Actual value C, 68.64; H, 9.40 Dimethylformamide (10 ml)-sulfolane (10 ml) containing p-toluenesulfonic acid (100 mg)
7-oxo-16-(2-hydroxy-3,4-dimethoxy-6-methylphenyl) in a mixed solvent of
Add hexadecanoic acid (1.75 g) and p-toluenesulfonyl hydrazide (930 mg) at 100°C. After 5 minutes, cyclohexane (10 ml) and sodium cyanoborohydride (1.0 g) are added. Incubate at 100℃ for 20 minutes. After returning to room temperature, add saturated brine (100 ml) and extract with ether (50 ml x 2). The ether layers are combined, washed with water, 1N hydrochloric acid, water again, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dissolved in chloroform and subjected to silica gel column chromatography. Elute with chloroform, collect fractions containing the target product, and distill off the solvent. Petroleum ether is added to the residual crystals, and the mixture is filtered after cooling. 16-(2-hydroxy-3,4
970 mg of -dimethoxy-6-methylphenyl)hexadecanoic acid are obtained. Melting point 45-46℃. Elemental analysis C 25 H 42 O 5 Calculated value C, 71.05; H, 10.02 Actual value C, 71.13; H, 10.13 Reference example 6 (1) 6-(9-chloroformylnonyl)-2,3-
Dimethoxy-5-methylphenylacetate (36.9 g) and 1-morpholino-1-cyclododecene (24.3 g) were mixed with triethylamine (14.3 ml).
The reaction is carried out in the same manner as in the step of Reference Example 5 in the presence of . The reaction product was treated with 6N hydrochloric acid (47ml), and the obtained 2-{10-(2-acetoxy-3,4-dimethoxy-6-methylphenyl)decanoyl}cyclododecanone (46.3g) was added to a 6N aqueous sodium hydroxide solution. to give 13-oxo-22-
(2-hydroxy-3,4-dimethoxy-6-
32.4 g of methylphenyl)docosanoic acid are obtained. Melting point 63-64℃. Elemental analysis As C 31 H 52 O 6 Calculated value C, 71.50; H, 10.07 Actual value C, 71.57; H, 10.17 (2) 13-oxo-22-(2-hydroxy-3,4
-dimethoxy-6-methylphenyl) docosanoic acid (5.21 g) and p-toluenesulfonic acid (250 g)
mg) and p-toluenesulfonylhydrazide (2.33 g) in a mixed solvent of dimethylformamide (25 ml)-sulfolane (25 ml)-cyclohexane (25 ml) in the same manner as in the step of Reference Example 5. The resulting crude product was recrystallized from methanol to give 22-(2-hydroxy-3,4
2.97 g of -dimethoxy-6-methylphenyl)docosanoic acid are obtained. Melting point 67-68℃. This product had all the same physicochemical constants as the crystal obtained in Reference Example 4. Elemental analysis As C 31 H 54 O 5 Calculated value C, 73.47; H, 10.74 Actual value C, 73.76; H, 10.08
Claims (1)
アルキル基を示す］で表わされるキノン類。[Claims] 1. General formula Quinones represented by [wherein n is an integer of 10 to 21 and R represents hydrogen or a lower alkyl group].
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4995680A JPS56147746A (en) | 1980-04-15 | 1980-04-15 | Quinones and their preparation |
| EP80302171A EP0021841B1 (en) | 1979-06-28 | 1980-06-27 | 2,3-dialkoxy-1,4-quinone derivatives; method of producing 1,4-quinone derivatives |
| DE8080302171T DE3069496D1 (en) | 1979-06-28 | 1980-06-27 | 2,3-DIALKOXY-1,4-QUINONE DERIVATIVES; METHOD OF PRODUCING 1,4-QUINONE DERIVATIVES |
| CA000355128A CA1135713A (en) | 1980-04-15 | 1980-06-30 | Quinone derivatives |
| US06/167,522 US4495104A (en) | 1980-04-15 | 1980-07-11 | Quinone carboxylic acids and ester derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4995680A JPS56147746A (en) | 1980-04-15 | 1980-04-15 | Quinones and their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56147746A JPS56147746A (en) | 1981-11-16 |
| JPH0115492B2 true JPH0115492B2 (en) | 1989-03-17 |
Family
ID=12845481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4995680A Granted JPS56147746A (en) | 1979-06-28 | 1980-04-15 | Quinones and their preparation |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US4495104A (en) |
| JP (1) | JPS56147746A (en) |
| CA (1) | CA1135713A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1986000887A1 (en) * | 1984-08-01 | 1986-02-13 | Takeda Chemical Industries, Ltd. | Quinone derivatives, process for their preparation, and medicinal composition containing the same |
| MX9203040A (en) * | 1984-08-01 | 1992-07-31 | Takeda Chemical Industries Ltd | DERIVATIVES OF QUINONA AND PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM. |
| US5304658A (en) * | 1984-08-01 | 1994-04-19 | Takeda Chemical Industries, Ltd. | Quinone derivatives, their production and use |
| ES2051841T3 (en) * | 1987-04-27 | 1994-07-01 | Takeda Chemical Industries Ltd | REDUCTION OF CARBOXYL ESTERS. |
| US4855085A (en) * | 1987-12-18 | 1989-08-08 | Hoffmann-La Roche Inc. | Asymmetric synthesis of natural vitamin E |
| US4914217A (en) * | 1987-12-18 | 1990-04-03 | Hoffmann-La Roche Inc. | Asymmetric synthesis of natural vitamin E |
| DE3842014A1 (en) * | 1988-12-14 | 1990-06-21 | Bayer Ag | METHOD FOR PRODUCING SULFOGROUPLE-FREE TRIPHENYLMETHANE DYES |
| KR100398055B1 (en) * | 2000-11-23 | 2003-09-19 | 한국화학연구원 | Quinone derivatives which exhibit antioxidant activity |
| EA016226B1 (en) * | 2005-06-01 | 2012-03-30 | Эдисон Фармасьютикалз, Инк. | Redox-active therapeutics for treatment of mitochondrial diseases |
| ES2823728T3 (en) * | 2005-09-15 | 2021-05-10 | Ptc Therapeutics Inc | Tail variants of therapeutic agents with redox activity for the treatment of mitochondrial diseases and other conditions and the modulation of energy biomarkers |
| EP1986636B1 (en) | 2006-02-22 | 2013-04-24 | Edison Pharmaceuticals, Inc. | Phenol and 1,4-benzoquinone derivatives for use in the treatment of mitochondrial diseases |
| JP2012502064A (en) | 2008-09-10 | 2012-01-26 | エジソン ファーマシューティカルズ， インコーポレイテッド | Treatment of pervasive developmental disorders with redox-active therapeutic agents |
| US8263094B2 (en) * | 2008-09-23 | 2012-09-11 | Eastman Chemical Company | Esters of 4,5-disubstituted-oxy-2-methyl-3,6-dioxo-cyclohexa-1,4-dienyl alkyl acids and preparation thereof |
| WO2017106803A1 (en) | 2015-12-17 | 2017-06-22 | Bioelectron Technology Corporation | Flouroalkyl, flouroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50148325A (en) * | 1974-05-02 | 1975-11-27 | ||
| JPS567734A (en) * | 1979-06-28 | 1981-01-27 | Takeda Chem Ind Ltd | Preparation of quinone derivative |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3849453A (en) * | 1970-03-17 | 1974-11-19 | Takeda Chemical Industries Ltd | Quinone derivatives |
| FR2235679B1 (en) * | 1973-07-02 | 1978-07-21 | Takeda Chemical Industries Ltd |
-
1980
- 1980-04-15 JP JP4995680A patent/JPS56147746A/en active Granted
- 1980-06-30 CA CA000355128A patent/CA1135713A/en not_active Expired
- 1980-07-11 US US06/167,522 patent/US4495104A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50148325A (en) * | 1974-05-02 | 1975-11-27 | ||
| JPS567734A (en) * | 1979-06-28 | 1981-01-27 | Takeda Chem Ind Ltd | Preparation of quinone derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| US4495104A (en) | 1985-01-22 |
| CA1135713A (en) | 1982-11-16 |
| JPS56147746A (en) | 1981-11-16 |
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